Activating mutations in G? proteins are the drivers of oncogenesis in numerous cancers. Therefore, identifying drugs that block the signaling pathways controlled by these mutations could have enormous therapeutic consequences. Uveal melanoma is a prototypical G?-driven cancer in which about 80% of tumors have activating mutations in one of two G?-encoding genes, GNAQ and GNA11. Although progress has been made in the treatment of primary uveal melanoma tumors, metastasis occurs in approximately 50% of patients and once the tumor has spread to other tissues and organs, usually the liver, no current treatments are effective and the disease is invariably fatal. Therefore, finding a treatment that reduces metastasis or can reduce tumor establishment or growth of metastatic uveal melanomas is of utmost importance, especially if the treatment also has therapeutic potential for several other cancers. Activating mutations in GNAQ and GNA11 control at least two major signaling pathways that are important for melanocyte transformation and uveal melanoma growth. These signaling pathways activate mitogen- activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) and YAP to control AP1- and YAP- TEAD-mediated transcription that leads to transformation and tumor growth. We and our collaborators at the University of Utah have identified the small GTPase ADP-ribosylation factor 6 (ARF6) as a primary immediate effector of constitutively activated GNAQ. Knocking down ARF6 expression or inhibiting its activation with the small molecule compound SecinH3 has the same effect as knocking down constitutively activated GNAQ. We have demonstrated that ARF6 knockdown inhibits the establishment and growth of tumors in an orthotopic xenograft mouse model of uveal melanoma and have preliminary data suggesting that small molecule inhibition of ARF6 likewise reduces tumor formation and growth. These results suggest that ARF6 inhibition may be an effective method for treating both primary and metastatic uveal melanoma. In this Phase I study, we will test our hypothesis by pursuing two aims. In Aim 1, we will determine whether novel ARF6 inhibitors can inhibit proliferation, anchorage-independent colony growth, and invasion of uveal melanoma cells. In Aim 2, we will test the efficacy of our inhibitors in our orthotopic xenograft model of human uveal melanoma. As noted above, G? proteins play important roles in many cancers. Therefore, results from this Phase I study may have much broader implications for the treatment of multiple cancers. Success will place us in an ideal position to proceed to a Phase II study in which we will continue to examine the efficacy of these compounds in other animal models of uveal melanoma to show general applicability, while also performing pharmacokinetic and detailed toxicity studies. These Phase II studies will be necessary to obtain IND approval and allow for future clinical trials.